The present invention relates to a drug delivery device and method for delivering a drug agent to a vessel or vessel-like lumen in the body. More particularly, the present invention relates to a drug delivery device and method wherein the drug agent is delivered to the vessel wall or to the outside of the vessel wall.
Obstructive atherosclerotic disease is a serious health problem facing our society today. This disease is the result of the deposit of fatty substances and cells and connective tissue on the interior of the walls of the arteries. The build-up or accumulation of such deposits results in a narrowing of the inside diameter of the artery which in turn restricts the blood flow through the artery. This disease, wherein the opening or lumen of the artery is narrowed, is known as atherosclerosis and the accumulation is known as a lesion.
One commonly used procedure for treating an obstruction caused by atherosclerosis is a procedure known as coronary artery bypass graft surgery ("bypass surgery"). Although bypass surgery has been used with moderate success in the treatment of atherosclerosis, it is invasive and traumatic to the patient.
One less invasive and traumatic procedure developed more recently is coronary angioplasty. Coronary angioplasty, and angioplasty in general, is a procedure in which a balloon is positioned in the inside of the artery at the site of the accumulation or lesion and inflated in order to dilate the atherosclerotic lesion and thus open the restricted area of the artery. In order to advance the balloon to the lesion, the balloon is attached to the distal end of a small diameter catheter, which includes means for inflating the balloon from the other end of the catheter. The catheter is maneuvered or "steered" through the patient's vessels to the site of the lesion with the balloon in an un-inflated form. When the un-inflated balloon is properly positioned at the lesion, the balloon is then inflated to dilate the restricted area.
While angioplasty has been relatively successful in treating coronary artery disease, restenosis of the treated site often occurs approximately 3 to 6 months following the procedure. It is believed that the primary factor in developing restenosis is the healing that takes place after the injury caused by the intervention of balloon dilation procedure. The restenosis has close analogy to scar formation following vascular surgery in that the histologic result has a similar morphology. The histologic response is called myointimal hyperplasia. The process of myointimal hyperplasia consists of the migration of smooth muscle cells through the internal elastic lamina into the vessel lumen where they then proliferate. The net result is a thickening of the vessel wall. Over time, this thickening re-occludes or re-stenoses the vessel to a point where it is clinically significant. That is, the blood flow through the vessel is diminished to a rate similar to the rate before the angioplasty procedure. The occurrence of this seems to happen approximately 30-35% of the time following an angioplasty to that specific site in coronary arteries.
Several alternative procedures have been attempted to try to affect the occurrence or rate of the restenosis following intervention to the lesion site in the coronary artery. These procedures have included the use of lasers, mechanical atherectomy devices, heated balloons, and metal implantable stents. While each of these procedures has shown some success in dealing with the initial lesion, all have the similar problem of restenosis at a similar or even greater occurrence. Current estimates of restenosis of the lesion site using these alternative procedures ranges between 40-50%. The time frame of restenosis of all of these is generally from 3-6 months after the procedure.
Therefore, it appears that this re-stenotic healing lesion area is independent of the type of interventional procedure used. Rather, it is a physiologic response to any type of injury brought to that lesion site. Because of this intervention independent physiologic response, it is felt by many physicians that potentially the best way to deal with restenosis would be by a pharmacologic means, such as a drug agent, targeted at the biochemical events that take place after injury.
To date, most pharmacologic trials involve either an oral or intravenously injected drug that is delivered throughout the whole body in hopes of trying to effect this small site in the arteries. This type of pharmacologic treatment is known as a "systemic treatment." Some agents that have been tried in human clinicals include: heparin, calcium channel blockers, angiotensin converting enzyme inhibitors, Omega-3 fatty acids, and growth peptides. Other agents that may not have been tried in clinicals but are of interest include thromboxane synthetase inhibitor, serotonin, growth factor inhibitors, growth factor analogs such as angiopeptin, antagonists, HMGCoA reductase inhibitors, platelet derived growth factor, inflammatory cell factors, platelet aggregation inhibitors, and thrombin inhibitors such as hirudin or its analogs.
The indication for use of most of these has been either in vitro-cell culture studies or animal studies. These studies have shown some effect on the smooth muscle cell proliferation and migration which are major components of the myointimal hyperplasia that takes place in the restenotic lesion. However, none of the systemic drug delivery human trials to date has shown a major effect on the occurrence of restenosis.
Even though none of these agents have been completely successful in the in-vivo human clinical trials, it is still generally felt that one of these agents or some other new agent, if delivered locally and site specifically to the lesion, would still be able to reduce the proliferative response. One of the problems with systemic techniques is the inability to deliver a high enough concentration of the agent locally at the lesion in order to effect the physiologic response. In the in-vitro and in-vivo animal studies which have shown some success, a high concentration of the agent was used. Thus, it is believed that if the agent was delivered specifically to the site as opposed to systemically, the agent may be delivered at a high enough concentration to truly effect the physiologic response.
The reason many of these agents have not been used in a higher concentration in-vivo in humans is that many of the agents may exhibit undesirable side effects. Thus, if a high concentration of the agents is given systemically, they may have unwanted physiologic effects. Therefore, if the drug can be given with high concentrations locally to the vessel wall while minimizing the systemic amount of drug, the desired result of modulating the restenotic growth while preventing any unwanted systemic effects may be achieved.
There are other ways known to date in trying to create a site specific local delivery of drug to a site. One approach presently contemplated is the use of a perforated or sweating balloon. For example, a drug delivery device is disclosed by Wolinsky, H., et al. in the article entitled, Use of a Perforated Balloon Catheter to Deliver Concentrated Heparin Into the Wall of a Normal Canine Artery, 15 JACC 475 (Feb. 1990). This device is a percutaneous transluminal coronary angioplasty (PTCA) balloon with several microholes in the balloon for delivery of an agent during balloon dilatation. The drug is incorporated into the same fluid which is used to inflate the balloon.
A disadvantage of available devices, such as the one disclosed by Wolinsky et al., is that these devices cause a substantial blockage of blood flow in the subject vessel during the procedure. Thus, such devices may only be used for the fairly short time frame (typically, from one to two minutes), similar to the time frame of the actual angioplasty dilatation.
Other available drug delivery devices are disclosed, for example, in U.S. Pat. No. 4,824,436 (Wolinsky) and U.S. Pat. No. 4,636,195 (Wolinsky). These devices are directed to a dual occlusion catheter in which a balloon is inflated proximally and distally of the accumulation or lesion creating a space for infusion of a drug. This dual balloon catheter creates a space for infusion of drug separate from the blood flow. This device, however, also can only be used for a short period of time because it occludes blood flow.
In these types of devices where a balloon is inflated inside the vessel, some means for providing perfusion through the catheter itself becomes important. It is necessary in such devices that the device provide a large latitude in time over which the agent could be delivered. Devices which occlude blood flow may not provide the necessary latitude. Because the basic research into the biochemistry and physiologic events indicate that the initial events begin immediately after injury and continue intensely for several hours, it is desirable for the drug delivery system to allow drug delivery for several hours to a day or two beginning immediately after intervention. This research also points out that the initial events subsequently create a cascade of events that ultimately lead to intimal thickening. While these accumulations or lesions do not become apparent for several months, it is felt that if these initial events can be modulated, blocked, or even accelerated, then the subsequent cascade can be altered and a diminished overall thickening could be achieved.
Some devices have been designed which permit localized delivery of a drug agent while providing enhanced perfusion capabilities. For example, the drug delivery catheter disclosed in co-pending U.S. patent application Ser. No. 07/740,045 filed on Aug. 2, 1991, commonly assigned to the Assignee of the present application, provides an inflatable perfusion lumen which provides significantly more perfusion area than previous drug delivery devices. The disclosed catheter and method also provides drug delivery pockets on the outer periphery of the perfusion lumen. The pockets allow the drug agent to be delivered site specifically for extended periods of time.
All of the drug delivery devices discussed above, however, require that the device remain in the vessel while the drug agent is being administered. It would be desirable to have a technique for delivering a drug agent locally without the need for the drug delivery device to remain in the vessel.
To this end, some techniques have been proposed wherein a drug is delivered by a surgical procedure where a drug agent is delivered to the outside of a vessel to be treated. Studies have shown that during administration by implanting a controlled release device which surrounds the vessel (periarterial drug administration) using drugs such as heparin-ethylenevinyl acetate significantly inhibited restenosis in an arterial injury model. See for example, Edelman et al., Proc. Natl. Acad. Sci. U.S.A., 87, 3773 (1990); and Edelman et al., J. Clin. Invest., 39, 65 (1992). In these types of procedures, access to the vessel is obtained by surgically cutting to the desired location in the vessel. Then the drug agent is maintained at the desired location by wrapping a band or cuff around the vessel with the agent being loaded into the band or cuff. Although periarterial drug administration has shown some initial success in an animal model, this procedure used for delivering the implant has the obvious disadvantage of being very invasive.
Therefore, it is desirable to have a drug delivery device capable of providing the necessary blood flow to the heart while the drug agent is being administered, which can be removed after the drug agent has been delivered and which is substantially less invasive than presently proposed techniques.
Such a device may also be extremely desirable in other procedures where a drug is to be delivered to a specific site in a vessel. For example, drug delivery devices may be useful in procedures where a drug or agent is used to dissolve the stenosis in an effort to avoid the use of angioplasty or atherectomy procedures altogether or to deliver a thrombolytic agent to dissolve a clot at the lesion site Such a device may also be useful in the treatment of various disorders involving other vessels or vessel-like lumens in the body.
It will be recognized from this discussion that there is a need for a generic type of drug delivery system which emphasizes physician control over the device and agent. The device should have flexibility as to the agent that is to be delivered and should be capable of delivering any number of agents (either separately or at the same time), or possibly also allow a change in the protocol of the delivery. It should also be flexible with respect to the time frame over which these agents would be delivered. It would also be desirable to have a device which can be removed from the vessel while the drug remains in place at the desired location.
Therefore, it is a primary object of the present invention to provide a device and method which can contain a relatively high concentration of a drug agent in a selected portion of a vessel, such as a blood vessel.
It is another object of the present invention to provide a device which can be removed after the agent has been delivered while the drug remains at the desired site.
It is a still further object of this invention to provide a device which is flexible as to the drug and the number of drugs or combination of therapeutic agents which can be delivered as well as the time frame over which they can be delivered.